Method and composition for the topical treatment of diabetic neuropathy

ABSTRACT

A method and composition for the treatment of diabetic neuropathy is disclosed. The composition comprises a cold compounded mixture of a compound that promotes synthesis of nerve growth factor, an aldose reductase inhibitor and an antioxidant formulated in a pharmaceutically acceptable carrier. It has been found that this combination of active agents provides significant, effective relief of the symptoms of diabetic neuropathy, as well as at least partial recovery of lost neurological function in some cases. In view of the consensus in the art that effective combinations of various active agents have not been demonstrated to be effective for the treatment of diabetic neuropathy, the present invention provides a surprising and unexpected effect. In addition, the topical compositions of the present invention, when used in effective amounts to treat diabetic neuropathy, do not exhibit the severe side effects of many prior art compositions proposed for treatment of this ailment, 
     In a second aspect, a method for the topical administration of a composition in accordance with the present invention for the treatment of diabetic neuropathy is disclosed. In the method, an effective amount of the composition of the invention is topically administered to the areas of the body that have been adversely affected by the diabetic neuropathy on a regular basis over a period of time sufficient to provide the beneficial effects of relief from the symptoms and at least some recover of the damaged nerve tissues.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method and composition for thetopical treatment of diabetic neuropathy. More particularly, the presentinvention relates to a topical composition including a combination ofingredients that provide a surprising degree of effective relief fromthe symptoms of diabetic neuropathy and to a method for administeringthe topical composition to treat diabetic neuropathy.

2. Description of the Prior Art

Diabetes mellitus is a common disease that is usually classified intoinsulin-dependent and non-insulin dependent types. Both types may bemanaged by diet, in combination with insulin in the first type and avariety of drugs in the second type. However, while the changes in bloodglucose associated with diabetes can usually be managed reasonablysatisfactorily by conscientious patients and doctors, this does notprevent long term damage to many tissues as a result of the disease.This damage may take many forms but the major types are damage to theeyes (retinopathy), nerves (neuropathy), kidneys (nephropathy) andcardiovascular system,

There are many approaches to reducing or preventing these forms ofdamage, which are collectively known as the long-term complications ofdiabetes. One approach is based on damage that results fromover-production of the glucose metabolite, sorbitol, in the cells of thebody, Glucose can be converted to sorbitol by the enzyme aldosereductase. High levels of sorbitol may be among the causes of diabeticcomplications such as diabetic neuropathy. As a result, a number ofpharmaceutical companies have been developing aldose reductaseinhibitors for the purpose of reducing diabetic neuropathy.

It has been established that a wide variety of flavanoids are effectiveinhibitors of aldose reductase, including such flavanoids as quercetin,quercetin and myrecetrin. However, U.S. Pat. No. 4,232,040 disclosesthat despite the fact that these flavanoids have been shown in in vitrostudies to be among the most potent flavanoids for aldose reductaseinhibition, a need exists for aldose reductase inhibitors that can bemore effectively used and in lower doses than the prior art compounds,including these flavanoids.

In fact, numerous patents are devoted to goal of developing improvedaldose reductase inhibitors. Among these patents are U.S. Pat. Nos.6,069,168; 5,011,840; 4,210,667; 4,147,795; 5,866,578; and 5,561,110.Numerous other patents also exist which relate to aldose reductaseinhibitors.

Another approach to the treatment of neuropathy is disclosed in U.S.Pat. No. 5,840,736 (Zelle et al.). In this method, pharmaceuticalcompositions for stimulating the growth of neurites in nerve cellscomprising a neurotrophic amount of a compound and a nerve growthfactor. These compositions may be administered in a number of waysincluding orally and topically.

Still another approach to the treatment of neuropathy is disclosed inU.S. Pat. No. 5,550,249 (Della Ville et al.). In this approach,compositions suitable for treatment of vitamin H deficiencies areadministered for the treatment of neuropathy. This patent relates tobiotin salts with alkanolamines. The compositions may be administeredorally, parenterally or topically.

U.S. Pat. No. 5,665,360 (Mann) relates to the treatment of peripheralneuropathies associated with diabetes mellitus by periodic topicalapplication of a composition containing capsicum oleoresin as the activeingredient. When applied to the skin of the affected area, pain andburning associated with the neuropathy are said to be reduced. However,capsicum oleoresin has been shown to kill nerve endings in some casesand thus this composition suffers from this disadvantage.

U.S. Pat. No. 5,981,594 (Okamoto et al.) relates to a method oftreatment of diabetic neuropathy using combined administration of aformulation including as an active ingredient, a prostaglandin Iderivative with an anti-diabetic agent in order to improve nerveconduction velocities. Suitable anti-diabetic agents include oralhypoglycemic agents and insulin.

The Okamoto patent also contains a detailed discussion of the varioustypes of neuropathy that may be associated with diabetes. According tothis patent, nerve conduction velocity (NCV) is the most widely usedmethod of objectively evaluating the severity of diabetic neuropathy.This patent also mentions that current methods of treating diabeticneuropathy such as dietetic therapy, administration of insulin,administration of aldose reductase inhibitors or aminoguaninidine toimprove abnormal glucose metabolism, administration of troglitazone oragents for the improvement of blood flow have been tested but found tobe insufficient when a single drug was used. Also, according to thispatent, methods of treatment by combined use of different therapeuticagents which have different functions had yet to be established. Thepatent concludes that combined drug therapies for diabetic neuropathy,aiming at recovering once reduced nerve conduction velocity, have notyet been confirmed.

There remains a need in the art for an effective treatment for diabeticneuropathy that does not suffer from the disadvantage that it causessevere side effects, as do many aldose reductase inhibitors, forexample.

Accordingly, it is the primary object of the present invention toprovide a topical composition that is effective for the treatment ofdiabetic neuropathy.

It is another object of the present invention to provide a topicalcomposition for the treatment of diabetic neuropathy which does notcause serve side effects in the patients treated with the composition.

These and other objects of the present invention will be apparent fromthe summary and detailed descriptions of the invention which follow.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to a topicalcomposition for the treatment of diabetic neuropathy. The compositioncomprises a cold compounded mixture of a compound that promotessynthesis of nerve growth factor, an aldose reductase inhibitor and anantioxidant formulated in a pharmaceutically acceptable carrier. It hasbeen found that this combination of active agents provides significant,effective relief of the symptoms of diabetic neuropathy, as well as atleast partial recovery of lost neurological function in some cases. Inview of the consensus in the art that effective combinations of variousactive agents have not been demonstrated to be effective for thetreatment of diabetic neuropathy, the present invention provides asurprising and unexpected effect. In addition, the topical compositionsof the present invention, when used in effective amounts to treatdiabetic neuropathy, do not exhibit the severe side effects of manyprior art compositions proposed for treatment of this ailment,

In a second aspect, the present invention relates to a method for thetopical administration of a composition in accordance with the presentinvention for the treatment of diabetic neuropathy. In the method, aneffective amount of the composition of the invention is topicallyadministered to the areas of the body that have been adversely affectedby the diabetic neuropathy on a regular basis over a period of timesufficient to provide the beneficial effects of relief from the symptomsand at least some recovery of the damaged nerve tissues.

In a third aspect, the present invention relates to a pharmaceuticallyacceptable carrier for topical compositions that provides excellentdispersions and/or solutions of active ingredients and good penetrationthrough the skin to the areas to be treated. The carrier for topicalcompositions may also include one or more materials that providebeneficial properties to the skin since many sufferers from diabeticneuropathy develop skin problems such as ulcers, lesions or cell damage.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a first aspect, the present invention relates to a topicalcomposition for the treatment of diabetic neuropathy. The compositionincludes a compound that promotes synthesis of nerve growth factor, analdose reductase inhibitor and an antioxidant formulated in apharmaceutically acceptable carrier for a topical composition.

The compound that promotes synthesis of nerve growth factor may beselected from suitable compounds that have been shown to have thisactivity. Suitable compounds that promote synthesis of nerve growthfactor are those that do not induce significant, adverse side effectswhen topically applied to a patient in amounts that promote synthesis ofnerve growth factor, and which do not react with one or more of theingredients of the topical composition resulting in a substantial lossof activity of one or more active ingredients. Preferred compounds forpromoting synthesis of nerve growth factor are those that occurnaturally in the human body and/or materials obtained from plants oranimal which may be ingested or topically applied by humans withoutsignificant, adverse side effects in the amounts used or derivativesthereof

Exemplary compounds that promote synthesis of nerve growth factor arevitamin D₃, vitamin D₃ derivatives such as 1(S),3(R)-dihydroxy-20(R)-(1-ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl)-9,10-seco-pregna-5(Z), 7(E), 10 (19)-triene. The preferred nerve growthfactor used in the topical composition is vitamin D₃. Also,pharmaceutically acceptable salts of the compounds that promotesynthesis of nerve growth factor may be employed.

The compound that promotes synthesis of nerve growth factor is used inan amount effective to promote the synthesis of nerve growth factor ofabout 10,000 to about 3 million IU. per kg of the composition. Morepreferably, the compound that promotes synthesis of nerve growth factoris employed in an amount of about 50,000 to about 2 million IU per kg ofthe composition, and most preferably an amount of 100,000 to about 1million IU is used per kg of the composition.

The preferred compounds that induce synthesis of nerve growth factormay, in addition to this activity, also function to prevent neurotrophicdeficits. This additional effect of the preferred compounds may alsocontribute to the overall beneficial effect of the topical compositionof the present invention.

In order to formulate the compound that promotes synthesis of nervegrowth factor in the topical composition of the present invention, itmay be necessary to use a dispersant. Suitable dispersant materials areknown to persons skilled in the art. A particularly suitable dispersantfor the compounds that promote synthesis of nerve growth factor is cornoil. Corn oil also has the advantage that it is a natural product. Theamount of corn oil used is an amount sufficient to disperse the compoundthat promotes synthesis of nerve growth factor.

The second active ingredient of the topical composition of the presentinvention is an aldose reductase inhibitor. Numerous suitable aldosereductase inhibitors are known to persons skilled in the art. Again,suitable aldose reductase inhibitors are those that do not inducesignificant, adverse side effects when topically applied to a patient inan amount effective for aldose reductase inhibition, and which do notreact with one or more of the ingredients of the topical compositionresulting in a substantial loss of activity of one or more activeingredients of the composition. Preferred aldose reductase inhibitorsare those that occur naturally in the human body and/or materialsobtained from plants or animal which may be ingested or topicallyapplied by humans without significant, adverse side effects in theamounts used or derivatives thereof

As mentioned above, numerous aldose reductase inhibitors are known topersons skilled in the art. However, significant adverse side effectsare associated with the use of many aldose reductase inhibitors inhumans. Thus, it is important to select one or more aldose reductaseinhibitors for use in the topical composition of the present inventionbased on minimizing the risk associated with use of the aldose reductaseinhibitor taking into account the amount of that particular inhibitorthat must be employed to achieve the desired level of aldose reductaseinhibition. Different aldose reductase inhibitors exhibit differentlevels of inhibition. With this in mind, the preferred aldose reductaseinhibitors for use in the topical compositions of the present inventionare flavonoids and flavonoid derivatives. Exemplary aldose reductaseinhibitors include (−)-epigallocatechin; (−)-epigallocatechin-gallate;1,2,3,6-tetra-o-gallyol-β-d-glucose; 2′o-acetylacetoside; 3,3′,4-tri-o-methyl-ellagic acid; 6,3′,4′-trihydroxy-5,7,8-trimethoxyflavone;6-hydroxy-luteolin; 6-hydroxykaempferol-3,6-dimethyl ether;7-o-acetyl-8-epi-loganic acid; acacetin; acetoside; acetyl trisulfatequercetin; amentoflavone; apiin; astragalin; avicularin; axillarin;baicalein; brazilin; brevifolin carboxylic acid; caryophyllene;chrysin-5,7-dihydroxyflavone; chrysoeriol; chrysosplenol;chrysosplenoside-a; chrysosplenoside-d; cosmosiin; δ-cadinene;dimethylmussaenoside; diacerylcirsimaritin; diosmetin; dosmetin; ellagicacid; ebinin; ethyl brevifolin carboxylate; flavocannibiside;flavosativaside; genistein; gossypetin-8-glucoside; haematoxylin;hispiduloside; hyperin; indole; iridine; isoliquiritigenin;isoliquiritin; isoquercitrin; jionoside; juglanin;kaempferol-3-rhamnoside; kaempferol-3-neohesperidoside; kolaviron;licuraside; linariin; linarin; lonicerin; luteolin;luetolin-7-glucoside; luteolin-7-glucoside; luetolin-7-glucoronide;macrocarpal-a; macrocarpal-b; macrocarpal-d; macrocarpal-g; maniflavone;methy scutellarein, naringenin; naringin; nelumboside; nepetin;nepetrin; nerolidol; oxyayanin-a; pectolinarigenin; pectolinarin;quercetagetin; quercetin; quercimertrin; quercitrin; quercitryl-2″acetate; reynoutrin; rhamnetin; rhoifolin; rutin; soutellarein;sideritoflavone; sophoricoside; sorbarin; spiraeoside; trifolin;vitexin; and wogonin. The most preferred flavonoid and/or flavonoidderivative aldose reductase inhibitors are quercetin, quercetrin,myricetin, kaempferol and myrecetrin since these compounds exhibit ahigh level of aldose reductase inhibition in combination with arelatively low toxicity. Also, pharmaceutically acceptable salts ofthese aldose reductase inhibitors may be employed.

The flavonoids and flavonoid derivatives are also preferred since someof these compounds may provide additional beneficial effects in thecomposition of the present invention. For example, quercetin may act asa chelator for transition metals that some studies have linked tocertain symptoms of diabetic neuropathy. Flavonoids may also have someanti-inflammatory activity and/or may help stabilize cell membranes,both of which activities may be beneficial in the treatment of diabeticneuropathy.

The aldose reductase inhibitor is used in an amount of about 2 to about40 grams per kg of the composition. More preferably, the aldosereductase inhibitor is employed in an amount of about 5 to about 30grams and most preferably an amount of 8 to about 20 grams per kg of thecomposition.

Another active ingredient in the composition of the present invention isthe antioxidant. The antioxidant may be a single compound or a mixtureof two or more compounds. Also, the antioxidant may include one or morecompounds that provide additional beneficial effects beyond theantioxidant activity, such as aldose reductase inhibition,

Compounds which may be used as antioxidants are those which exhibitantioxidant activity when administered topically without causing anysevere adverse side affect when used in an amount effective to providesufficient antioxidant activity, and which do not react with one or moreof the ingredients of the topical composition resulting in a substantialloss of activity of one or more active ingredients. Preferredantioxidants are those that occur naturally in the human body and/ormaterials obtained from plants or animal which may be ingested ortopically applied by humans without significant, adverse side effects inthe amounts used or derivatives thereof

More preferred antioxidants are selected from ascorbyl palmitate,ascorbic acid (vitamin C), vitamin A, vitamin E acetate, α-lipoic acid,especially DL-α-lipoic acid, coenzyme Q10, glutathione, catechin,glangin, rutin, luteolin, morin, fisetin, silymerin, apigenin,gingkolides, hesperitin, cyanidin, citrin and derivatives thereof whichexhibit antioxidant activity. Even more preferably, mixtures of two ormore antioxidants are employed in the composition of the presentinvention. Particularly preferred antioxidant mixtures are ascorbylpalmitate with one or both of vitamin A and vitamin E acetate. Theantioxidants may also be used in the form of their pharmaceuticallyacceptable salts and this may be preferred in some cases to increasesolubility or dispersability, to reduce adverse side effects, etc.

The antioxidant is used in an amount of about 1 to about 50 grams per kgof the composition. More preferably, the antioxidant is employed in anamount of about 2 to about 30 grams, and most preferably an amount ofabout 5 to about 20 grams per kg of the composition.

The antioxidants used in the composition of the present invention arepreferably selected not only for their antioxidant activity, but alsobased on other beneficial effects that particular compounds may provide.For example, ascorbyl palmitate not only has antioxidant activity, butalso may act as an aldose reductase inhibitor and may help preventdegradation of nitric oxide (NO) and thus is a particularly preferredantioxidant for the present invention. Similarly, vitamin E may alsohelp prevent degradation of nitric oxide and is thus a preferredantioxidant. Vitamin A is a fat-soluble material and thus is preferredfor use due to this additional beneficial property. However, due to itssolubility characteristics, vitamin A may need to be formulated in asuitable dispersant such as corn oil in much the same manner as vitaminD₃ as described above,

Suitable additional beneficial properties for compounds useful in thecompositions of the present invention include absorbability when appliedtopically, aldose reductase inhibition, antioxidant properties, freeradical scavenging, transition metal chelation, nitric oxidestabilization, and anti-inflamatory activity.

The compositions in accordance with the present invention may provideone or more of the following beneficial effects to a patient whentopically applied in effective amounts; relief of pain, burning,tingling, electrical sensations and/or hyperalgesia, increasedmicrocirculation, nitric oxide stabilization, promotes healing of skinulcers and lesions, protein kinase C inhibition, decreased oxidativestress, anti-inflammation, protection against radiation damage,particularly ultraviolet radiation, blockage of the formation ofleukotrienes, stabilization of cell membranes, and promotion of thesynthesis of nerve growth factor.

The method of the present invention involves the topical application ofa composition of the present invention to areas of the skin in thevicinity of tissue that suffers from diabetic neuropathy. In particular,the present invention is useful on the patients' extremities such as thefingers, toes, hands and feet where diabetic neuropathy is often themost pervasive.

In the method, a suitable amount of the composition of the invention isapplied one to six times daily as needed to relieve pain and othersymptoms of the diabetic neuropathy. Preferably, the composition isapplied two to four times daily, as needed for pain. A sufficient amountshould be applied to cover the area afflicted with the diabeticneuropathy with a thin layer of the composition and the compositionshould be rubbed into the skin until little or no residue remains on theskin. Treatment begins initially to treat acute symptoms but may becontinued indefinitely to relieve pain, prevent symptoms of diabeticneuropathy from returning and possibly restore some nerve and/or skinfunction.

The method of the present invention may provide one or more of thebeneficial effects described above for the compositions of theinvention. In addition, the method of the present invention may providesome additional beneficial effects due to one or more of the ingredientscontained in the pharmaceutically acceptable carrier as described inmore detail below,

The pharmaceutically acceptable carrier of the present invention issuitable for use as a carrier for topical compositions wherein theactive ingredients are dissolved, dispersed and/or suspended in thecomposition. The carrier of the present invention contains at least ahydrophilic ointment base, panthenol or a panthenol derivative and adispersant if needed to disperse one or more insoluble or partiallyinsoluble active ingredients in the carrier.

Suitable hydrophilic ointment bases are known to persons skilled in theart. Exemplary hydrophilic ointment bases suitable for use in thepresent invention are non-U.S.P. hydrophilic ointment bases such asthose made by Fougera, Inc. Sufficient hydrophilic ointment base isemployed to act as a Garrier for the active ingredients of thecomposition. Typically the hydrophilic ointment base will make up morethan about 80% of the total composition and more preferably about 80-90%of the composition is the hydrophilic ointment base. The hydrophilicointment base functions as a carrier and enhances penetration into theskin.

The panthenol or panthenol derivatives useful in the present inventioninclude at least D-panthenol, DL-panthenol and mixtures hereof Thiscomponent of the carrier has skin moisturizing properties and acts as aquick, deep penetrating component of the carrier that helps deliver theactive ingredients through the skin to the area to be treated andimparts a healing effect to damaged tissue. The amount of panthenol orpanthenol derivative to be employed is from about 0.25 to about 10weight percent, more preferably from about 0.5 to about 5 weight percentand most preferably from about 1 to about 2 weight percent, based on thetotal weight of the composition.

The carrier of the present invention may also include additionalingredients such as other carriers, moisturizers, humectants, emollientsdispersants, radiation blocking compounds, particularly UV-blockers, aswell as other suitable materials that do not have a significant adverseeffect on the activity of the topical composition. Preferred additionalingredients for inclusion in the carrier are sodium acid phosphatemoisturizer, witch hazel extract carrier, glycerine humectant, apricotkernal oil emollient, and corn oil dispersant.

Other materials which may optionally be included in the topicalcompositions of the present invention include inositol, other B-complexvitamins, and anti-inflammatory agents. The composition of the presentinvention may also be employed to facilitate wound healing, for thetreatment of skin cancer and/or one or more symptoms thereof or as acomposition for protecting skin from the harmful effects of radiationsuch as radiation breakdown.

The composition of the present invention is made by cold compounding.This is an important feature of the invention since one or more of thecompounds employed in the topical composition are sensitive to heat orother types of energy and thus the activity of the composition may bedetrimentally affected as a result of the formulation of thecompositions in other manners. Thus, the ingredients of the topicalcomposition the present invention are merely mixed together, withoutheating using a sufficient amount of the carrier to provide asubstantially homogeneous cream or ointment. It may be necessary todissolve, disperse or suspend one or more of the ingredients prior tocold compounding in order to ensure substantially homogeneousdistribution of the active ingredients in the composition.

A preferred composition of the invention can be made using the followingingredients, all based on use of one pound of hydrophilic ointment base.25-35 cc of a 50% aqueous solution of sodium acid phosphate moisturizingagent, 5-10 cc of D- or DL-panthenol, 5-10 cc of glycerine, 1-3 cc ofapricot kernal oil, 3-5 cc of a dispersion of vitamins A and D₃ in acorn oil base, 10-20 cc of witch hazel extract, 0.5-2 cc of vitamin Eacetate, 2-4 grams of ascorbyl palpitate and 4-8 grams of quercetinpowder. Optionally, one or more of the glycerin, witch hazel extract,vitamins A and E and/or the ascorbyl palmitate can be reduced oreliminate from a particular composition, if desirable or larger amountsof one type of component, i.e. antioxidant, can be employed whilereducing the amount of another component of the same type or having asimilar type of activity,

The invention will now be further illustrated by the following example.

EXAMPLE 1

A topical composition including a mixture of an hydrophilic ointmentbase, sodium acid phosphate moisturizing agent, a witch hazel extractcarrier, glycerine, apricot kernal oil and DL-panthenol as thepharmaceutically acceptable carrier and vitamins A and D₃, ascorbylpalmitate, quercetin and vitamin E acetate was prepared by coldcompounding. The formulation of the composition is given in Table 1.

The composition was prepared by first placing the hydrophilic ointmentbase in a stainless steel bowl and mixing briskly until the ointmentbecomes creamy. Then, the sodium acid phosphate, panthenol, ascorbylpalmitate, glycerine, apricot kernal oil, vitamins A and D₃, witch hazelextract, vitamin E acetate and quercetin are added in that order. Aftereach ingredient is added, mixing is continued until all traces of dryingredients have disappeared and a substantially homogeneous mixture isobtained. The final color should be a consistent yellow and the creamshould have the consistency of cake frosting. The mixture is then placedin a sterile container. All containers which contact the compositionduring mixing must also be sterilized with, for example, zephiranchoride or a chlorox solution such as betadine.

This composition was topically administered, under the supervision of aphysician, to several patients diagnosed with the most difficult casesof diabetic peripheral neuropathy. The topical composition was appliedtwice daily in the morning and afternoon, except that patients werepermitted to apply the composition up to six times daily, as needed forpain relief over a period of a few days. All of the eight patientstreated experienced immediate positive results that lasted up to a dayor two after treatment was discontinued. The effects noted by thepatients included the relief of burning pain, tingling, healing ofdamaged skin, and reversal of skin discoloration due to impairedcirculation.

TABLE 1 Ingredient Amount Employed Hydrophilic ointment base  1 pound50% aqueous solution of Sodium acid phosphate 25 cc DL-panthenol  5 ccGlycerine  5 cc Apricot kernal oil  3 cc Witch hazel extract 12 ccVitamin E acetate  1 cc Ascorbyl Palmitate  2 grams Quercetin powder  4grams

The foregoing detailed description of the invention and examples are notintended to limit the scope of the invention in any way and should notbe construed as limiting the scope of the invention. The scope of theinvention is to be determined from the claims appended hereto.

What is claimed is:
 1. A topical composition for the treatment ofdiabetic neuropathy by application to the skin, which comprises a coldcompounded mixture of an amount of a compound that promotes synthesis ofnerve growth factor which is effective when administered topically tothe skinto promote synthesis of nerve growth factor, an amount of analdose reductase inhibitor which is effective when administeredtopically to the skin to inhibit aldose reductase and an effectiveamount of an antioxidant, formulated in a pharmaceutically acceptablecarrier for a topical composition.
 2. A topical composition as claimedin claim 1, wherein the compound that promotes the synthesis of nervegrowth factor is selected from the group consisting of: vitamin D₃,1(S), 3(R)-dihydroxy-20(R)-(1-ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl)-9, 10-seco-pregna-5(Z), 7(E),10 (19)-triene, and other vitamin D₃ derivatives which promote thesynthesis of nerve growth factor, pharmaceutically acceptable saltsthereof and mixtures thereof.
 3. A topical composition as claimed inclaim 1, wherein the aldose reductase inhibitor is selected from thegroup consisting of: flavonoids, flavonoid derivatives which exhibitaldose reductase inhibiting properties, pharmaceutically acceptablesalts thereof and mixtures thereof.
 4. A topical composition as claimedin claim 3, wherein the aldose reductase inhibitor is selected from thegroup consisting of: (−)-epigallocatechin; (−)-epigallocatechin-gallate;1,2,3,6-tetra-o-gallyol-β-d-glucose; 2′o-acetylacetoside;3,3′,4-tri-o-methyl-ellagic acid;6,3′,4′-trihydroxy-5,7,8-trimethoxyflavone; 6-hydroxy-luteolin;6-hydroxykaempferol-3,6-dimethyl ether; 7-o-acetyl-8-epi-loganic acid;acacetin; acetoside; acetyl trisulfate quercetin; amentoflavone; apiin;astragalin; avicularin; axillarin; baicalein; brazilin; brevifolincarboxylic acid; caryophyllene; chrysin-5,7-dihydroxyflavone;chrysoeriol; chrysosplenol; chrysosplenoside-a; chrysosplenoside-d,cosmosiin; δ-cadinene; dimethylmussaenoside; diacerylcirsimaritin;diosmetin; dosmetin; ellagic acid; ebinin; ethyl brevifolin carboxylate;flavocannibiside; flavosativaside; genistein; gossypetin-8-glucoside;haematoxylin; hispiduloside; hyperin; indole; iridine;isoliquiritigenin; isoliquiritin; isoquercitrin; jionoside; juglanin;kaempferol-3 -rhamnoside; kaempferol-3-neohesperidoside; kolaviron;licuraside; linariin; linarin; lonicerin; luteolin;luetolin-7-glucoside; luteolin-7-glucoside; luetolin-7-glucoronide;macrocarpal-a; macrocarpal-b; macrocarpal-d; macrocarpal-g; maniflavone;methy scutellarein; naringenin; naringin; nelumboside; nepetin;nepetrin; nerolidol; oxyayanin-a; pectolinarigenin; pectolinarin;quercetagetin; quercetin; quercimertrin; quercitrin; quercitryl-2″acetate; reynoutrin; rhamnetin; rhoifolin; rutin; scutellarein;sideritoflavone; sophoricoside; sorbarin; spiraeoside; trifolin;vitexin; wogonin; pharmaceutically acceptable salts thereof, andmixtures thereof.
 5. A topical composition as claimed in claim 3,wherein the aldose reductase inhibitor comprises at least one compoundselected from the group consisting of: quercetin, quercetrin, myricetin,kaempferol and myrecetrin.
 6. A composition as claimed in claim 1,wherein the antioxidant comprises at least one compound selected fromthe group consisting of: ascorbyl palmitate, ascorbic acid, vitamin A,vitamin B acetate, α-lipoic acid, coenzyme Q10, glutathione, catechin,glangin, rutin, luteolin, morin, fisetin, silymerin, apigenin,gingkolides, hesperitin, cyanidin, citrin, derivatives thereof whichexhibit antioxidant activity, and pharmaceutically acceptable saltsthereof.
 7. A topical composition as claimed in claim 6, wherein theantioxidant comprises a mixture of at least two different compounds. 8.A topical composition as claimed in claim 1, wherein the antioxidantcomprises vitamin E acetate.
 9. A topical composition as claimed inclaim 1, wherein the antioxidant comprises vitamin A.
 10. A topicalcomposition as claimed in claim 1, wherein the antioxidant comprisesascorbyl palmitate.
 11. A topical composition as claimed in claim 8,wherein the antioxidant further comprises at least one compound selectedfrom the group consisting of ascorbyl palmitate and vitamin A.
 12. Atopical composition as claimed in claim 5, wherein the compound thatpromotes the synthesis of nerve growth factor comprises vitamin D₃. 13.A topical composition as claimed in claim 12, wherein the antioxidantcomprises at least one compound selected from the group consisting ofvitamin A, vitamin E acetate, and ascorbyl palmitate.
 14. A topicalcomposition as claimed in claim 13, wherein the antioxidant comprisesvitamin A, vitamin E acetate and ascorbyl palmitate and the aldosereductase inhibitor comprises quercetin.
 15. A topical composition asclaimed in claim 1, wherein the pharmaceutically acceptable carriercomprises an amount of an additive selected from the group consistingof: D-panthenol, DL-panthenol and mixtures thereof, that is sufficientto promote penetration of the topical composition into the skin.
 16. Atopical composition as claimed in claim 1, wherein the pharmaceuticallyacceptable carrier comprises a sufficient amount of at least onenon-U.S.P. hydrophilic ointment base to form an homogeneous mixture ofthe active ingredients of the topical composition.
 17. A topicalcomposition as claimed in claim 16, wherein the pharmaceuticallyacceptable carrier fiber comprises sodium acid phosphate.
 18. A topicalcomposition according to claim 1, wherein the antioxidant comprisesDL-α-lipoic acid.